The goal of this project, for which we now request funding for grant years 11-15, is to support continuing methodologic research and secondary data-analysis in order to (i) better understand the joint and interactive effects of genes and environment in determining differences in alcoholism risk, the course of drinking patterns and alcohol problems through time, and the sequelae of alcohol problems, and (ii) stimulate and refine the implementation of new research approaches to address these questions. Major areas of focus will include (a) the attempted identification of alcoholism subtypes, or stages in the progression of alcoholic symptoms, (b) the extension of this work within an event history framework, to examine genetic and environmental influences on probability of transition from social problem drinking, or from mild to severe dependence, (c) the testing of potential mediators of genetic influences on alcoholism risk, including GE correlation effects, (d) the testing of risk-modifiers (e.g. genotype x environment interaction effects), (e) the use of genetically informative high-risk sampling designs to investigate more efficiently the ways in which genetic differences lead to differences in alcoholism risk (e.g. challenge studies of alcohol sensitivity; e.g. QTL-mapping studies), (f) the use of genetically informative designs to investigate the sequelae of alcoholism. Secondary data-analyses will be used for 'reality-testing' of methodologic research, principally utilizing data-bases from alcohol- related studies of the Australian twin panel, maintained via subcontract to QIMR. These studies have generated diagnostic interview data on some 9000 twins and 3500 spouses of twins, as well as questionnaire measures (N is greater than 20,000) on twins and a subsample of their relatives (siblings, spouses, parents and adult children) and, for a subsample of twins, alcohol challenge measures (obtained in 1979-81), genotype data (ADH2, ADH3) and biochemical markers of drinking. The data thus permit analyses of the multiple pathways by which genetic differences between individuals, and differences in environmental exposure, lead to differences in alcoholism risk, leading to predictions that can be tested in future and ongoing studies.